A prophylactic vaccine remains the best hope for dramatically reducing the number of new human immunodeficiency virus (HIV) infections. The primary goal of this application is to learn whether cellular immune responses contribute to the success of attenuated vaccines by adoptively transferring these cells from immunized animals into naive recipients that are subsequently challenged with pathogenic simian immunodeficiency virus (SIV). The animals in this proposal can also be studied with new sequencing technology to better understand how and why HIV/SIV adapt to their hosts, possibly identifying new targets for prophylactic or therapeutic intervention. We are the only laboratory with the immunologic, genetic, and virologic tools to use adoptive transfers to define the correlates of immunity elicited by attenuated SIV. Demonstrating that lymphocytes present at the time of virus challenge (but not long thereafter) influence viral setpoint could radically change the way vaccine and pathogenesis studies are interpreted. Moreover, using Roche/454 pyrosequencing to sequence entire SIV genomes will allow us to quantify the emergence of viral variants and perturbations in the virus population with unprecedented sensitivity. This work is currently in its infancy; methods to generate hundreds of sequences at each nucleotide site in HIV and SIV genomes were pioneered in our lab very recently. We will improve this technology by forging interdisciplinary collaborations with computer scientists and statisticians in order to develop better ways to analyze and visualize massive amounts of data generated for each genome. SPECIFIC AIMS These aims will test the hypothesis that adoptively transferred cells from donors immunized with attenuated SIV establish conditions favorable for long-term immunologic containment of pathogenic SIV and, in the process, fundamentally advance our understanding of SIV sequence dynamics: 1) We will determine whether bulk lymphocytes transferred from SIVmac239?nef immunized donors significantly decrease setpoint SIVmac239 viremia. 2) We will characterize the evolutionary dynamics of SIVmac239 using genome-wide Roche/454 pyrosequencing. PERSPECTIVE We are uniquely positioned to continue our pioneering studies with nonhuman primate adoptive transfers and viral sequencing. Productivity in the first two years of this R01 has been exceptional and augurs well for the successful completion of this ambitious project.